We wish to establish the molecular basis of the scirrhous reaction to human breast carcinoma. It is not known whether this fibrotic response is due to the host stromal cells, the malignant epithelial cells or is perhaps dependent on an interaction between these two cell types. Tumor cells exert an influence on the neighboring host stromal cells. We maintain that this influence is exerted in part through the extracellular matrix of the tumor cells. When normal human fibroblasts are plated on a preformed matrix of human breast cancer cells, a series of remarkable changes occur. The matrix of breast cancer cells is mitogenic for the fibroblasts. Fibroblasts grow in whorls and ridges, grow to higher density, and appear to lose normal contact inhibition. They show some of the properties of transformed cells. They begin to synthesize type V collagen and basement membrane-specficic type IV collagen. There is stimulation of elastin deposition. They may also undergo myofibroblast differentiation. Fibroblasts undergo a five-fold increase in proteoglycan synthesis under the influence of the tumor matrix. All of these tissue culture reactions taken together appear to simulate the in vivo scirrhous response to breast cancer and may be the basis of that reaction. The purpose of this proposal is to explore these phenomena, to document them by a combined biochemical and morphological approach. Finally, we propose to isolate the components of the tumor cell matrix and to identify those macromolecules which are informational for the fibroblast. Our ultimate goal is to determine the mechanism by which such information is perceived and processed, or perhaps misperceived and misprocessed, by the normal stromal cells of the host. The answers to such questions together with our studies on the enzymes which degrade the matrix will reveal much about the tactics used by malignant cells for growth and invasion.